This core is designed to establish a facility and procedures for definitively testing whether an intervention treatment alters the rate of brain aging in rodent models. Although the NIA supports a Consortium that runs intervention clinical trials for select agents, there is growing recognition of a need for additional testing programs at the preclinical level. However, critical putative mechanisms and hypotheses of brain aging and AD are emerging from this PPG and elsewhere that warrant systematic testing. Long-term interventions are essentially the only way to test whether an experimental intervention alters the rate of gradual processes of aging and age-related pathology. Thus, there is a need for an intervention program that focuses on animal models of brain aging and AD. The program project has two parallel longitudinal components (at Universities of Kentucky and Alabama) and will assess the effectiveness of "intervention treatments" in slowing the progression or alleviating aspects of brain aging and cognitive decline in a rat model of aging (F344 rats) and in a mouse model of AD (APP/PS1 mice). In F344 rats, the long-term interventions will be initiated at middle age, prior to the onset of cognitive decline. The same approach will be used in APP/PS1 mice. However, because of the accelerated pathology of this model, treatment will begin at 3 months, prior to cognitive decline and the appearance of pathological markers. The treatments chosen are compatible with long-term exposure and have few side effects. The four initial agents (minocycline, memantine, vitamin D, lipoic acid) test key hypotheses in various Projects of the PPG. All have compelling evidence for their potential efficacy against processes involved in aging and are currently approved for other indications in humans. A search of the clinical trials web site or the NIH CRISP database of sponsored grants reveals that none of these interventions are currently in clinicai/preciinical trial as aging interventions. Our use of these existing therapies as potential aging interventions, therefore, represents a novel use of these treatments. Thus, these candidate interventions appear to be highly feasible and there is substantial evidence indicating potentially favorable outcomes. Importantly, the selection of these agents for long-term tests is hypothesisdriven and will directly advance the aims of multiple Projects within the program project.